Gastrectomy with or without omentectomy for cT3-4 gastric cancer: a multicentre cohort study.

BACKGROUND: Omentectomy is performed widely for locally advanced gastric cancer to prevent disease recurrence. However, its clinical benefit is unknown. METHODS: This retrospective cohort study compared the outcome of gastrectomy with preservation of the omentum (GPO) and gastrectomy with resection of the omentum (GRO) among patients with cT3-T4 gastric cancer who underwent gastrectomy between 2006 and 2012 in one of five participating institutions. A consensus conference identified 28 variables potentially associated with outcome after gastrectomy for the estimation of propensity scores, and propensity score matching (PSM) was undertaken to control for possible confounders. Postoperative surgical outcomes, overall survival and disease recurrence were compared between GPO and GRO. RESULTS: A total of 1758 patients were identified, of whom 526 remained after PSM, 263 in each group. Median follow-up was 4·9 (i.q.r. 3·1-5·9) years in the GRO group and 5·0 (2·5-6·8) years in the GPO group. The incidence of postoperative complications of Clavien-Dindo grade III or more was significantly higher in the GRO group (17·5 versus 10·3 per cent; P = 0·016). Five-year overall survival rates were 77·1 per cent in the GRO group and 79·4 per cent in the GPO group (P = 0·749). There were no significant differences in recurrence rate or pattern of recurrence between the groups. CONCLUSION: Overall survival and disease recurrence were comparable in patients with cT3-4 gastric cancer who underwent GPO or GRO.

ANTECEDENTES: La omentectomía se realiza ampliamente en el cáncer gástrico localmente avanzado para prevenir la recidiva de la enfermedad. Sin embargo, se desconoce su beneficio clínico. MÉTODOS: Este estudio retrospectivo comparó el resultado de la gastrectomía con preservación del omento (gastrectomy with preservation of the omentum, GPO) con la gastrectomía con resección del omento (gastrectomy with resection of the omentum, GRO) para el cáncer gástrico con estadio clínico T3/T4. Se incluyeron pacientes sometidos a gastrectomía por cáncer gástrico clínico T3/T4 (2006-2012) y se recogieron datos relevantes de 5 hospitales participantes. A través de una conferencia de consenso se identificaron 28 variables potencialmente asociadas con el resultado tras la gastrectomía, mediante las cuales se estimaron las puntuaciones de propensión, utilizándose el emparejamiento por puntuación de propensión (propensity score matching, PSM) para el control de posibles factores de confusión. Los resultados quirúrgicos postoperatorios, la supervivencia global y la recidiva de la enfermedad se compararon entre las gastrectomías con GPO y GRO. RESULTADOS: En total, se identificaron 1.758 pacientes, seleccionándose 526 (263 GRO y 263 GPO) tras el PSM. La mediana (rango intercuartílico) de seguimiento fue de 4,9 años (3,1-5,9) en el grupo GRO y de 5,0 años (2,5-6,8) en el grupo GPO. La incidencia de complicaciones postoperatorias de Clavien-Dindo grado III o más alto fue significativamente más elevada en el grupo GRO que en el grupo GPO (17,1% versus 9,1%; P = 0,010). La supervivencia global a los 5 años fue del 77,1% para el grupo GRO y del 79,4% para el grupo GPO (P = 0,749). No hubo diferencias estadísticamente significativas en la tasa de recidiva o patrón de recidiva entre ambos grupos. CONCLUSIÓN: La supervivencia global y la recidiva de la enfermedad son comparables en pacientes con cáncer gástrico estadio clínico T3-4 sometidos a GPO o GRO.

12-OH-17,18-Epoxyeicosatetraenoic acid alleviates eosinophilic airway inflammation in murine lungs.

BACKGROUND: Asthma is characterized by airway inflammation and obstruction with eosinophil infiltration into the airway. Arachidonic acid, an omega-6 fatty acid, is metabolized into cysteinyl leukotriene with pro-inflammatory properties for allergic inflammation, whereas the omega-3 fatty acid eicosapentaenoic acid (EPA) and its downstream metabolites are known to have anti-inflammatory effects. In this study, we investigated the mechanism underlying the counter-regulatory roles of EPA in inflamed lungs. METHODS: Male C57BL6 mice were sensitized and challenged by ovalbumin (OVA). After EPA treatment, we evaluated the cell count of Bronchoalveolar lavage fluid (BALF), mRNA expressions in the lungs by q-PCR, and the amounts of lipid mediators by liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidomics. We investigated the effect of the metabolite of EPA by in vivo and in vitro studies. RESULTS: Eicosapentaenoic acid treatment reduced the accumulation of eosinophils in the airway and decreased mRNA expression of selected inflammatory mediators in the lung. Lipidomics clarified the metabolomic profile in the lungs. Among EPA-derived metabolites, 12-hydroxy-17,18-epoxyeicosatetraenoic acid (12-OH-17,18-EpETE) was identified as one of the major biosynthesized molecules; the production of this molecule was amplified by EPA administration and allergic inflammation. Intravenous administration of 12-OH-17,18-EpETE attenuated airway eosinophilic inflammation through downregulation of C-C chemokine motif 11 (CCL11) mRNA expression in the lungs. In vitro, this molecule also inhibited the release of CCL11 from human airway epithelial cells stimulated with interleukin-4. CONCLUSION: These results demonstrated that EPA alleviated airway eosinophilic inflammation through its conversion into bioactive metabolites. Additionally, our results suggest that 12-OH-17,18-EpETE is a potential therapeutic target for the management of asthma.

Circulatory CNP Rescues Craniofacial Hypoplasia in Achondroplasia.

Achondroplasia is the most common genetic form of human dwarfism, characterized by midfacial hypoplasia resulting in occlusal abnormality and foramen magnum stenosis, leading to serious neurologic complications and hydrocephalus. Currently, surgery is the only way to manage jaw deformity, neurologic complications, and hydrocephalus in patients with achondroplasia. We previously showed that C-type natriuretic peptide (CNP) is a potent stimulator of endochondral bone growth of long bones and vertebrae and is also a potent stimulator in the craniofacial region, which is crucial for midfacial skeletogenesis. In this study, we analyzed craniofacial morphology in a mouse model of achondroplasia, in which fibroblast growth factor receptor 3 (FGFR3) is specifically activated in cartilage ( Fgfr3ach mice), and investigated the mechanisms of jaw deformities caused by this mutation. Furthermore, we analyzed the effect of CNP on the maxillofacial area in these animals. Fgfr3ach mice exhibited midfacial hypoplasia, especially in the sagittal direction, caused by impaired endochondral ossification in craniofacial cartilage and by premature closure of the spheno-occipital synchondrosis, an important growth center in craniomaxillofacial skeletogenesis. We crossed Fgfr3ach mice with transgenic mice in which CNP is expressed in the liver under the control of the human serum amyloid-P component promoter, resulting in elevated levels of circulatory CNP ( Fgfr3ach/SAP-Nppc-Tg mice). In the progeny, midfacial hypoplasia in the sagittal direction observed in Fgfr3ach mice was improved significantly by restoring the thickness of synchondrosis and promoting proliferation of chondrocytes in the craniofacial cartilage. In addition, the foramen magnum stenosis observed in Fgfr3ach mice was significantly ameliorated in Fgfr3ach/SAP-Nppc-Tg mice due to enhanced endochondral bone growth of the anterior intraoccipital synchondrosis. These results clearly demonstrate the therapeutic potential of CNP for treatment of midfacial hypoplasia and foramen magnum stenosis in achondroplasia.

Comparison of human mesenchymal stem cells derived from bone marrow, synovial fluid, adult dental pulp, and exfoliated deciduous tooth pulp.

Populations of pluripotent stem cells were isolated from bone marrow, synovial fluid, adult dental pulp, and exfoliated deciduous teeth and their multipotentiality properties compared. Osteogenic, chondrogenic, adipogenic, and neurogenic differentiation potentials were examined. Bone marrow mesenchymal stem cells (BMMSCs) and synovial fluid-derived cells (SFCs) showed the highest levels of osteogenesis as expressed by alkaline phosphatase (ALP) activity (0.54±0.094 U/mg protein and 0.57±0.039 U/mg protein, respectively; P=0.60) and by osteocalcin (BGLAP; determined by real-time RT-PCR). SFCs showed the highest levels of chondrogenesis as expressed by ALP activity (1.75±0.097 U/mg protein) and of COL2A1 and COL10A1 by real-time PCR. In terms of adipogenesis, lipid vesicles were observed in the BMMSCs and SFCs. Dental pulp stem cells (DPSCs) and stem cells from human exfoliated deciduous teeth (SHED) exhibited neurogenesis potential, as shown by increases in expression of class III ß-tubulin (TUBB3) and microtubule-associated protein 2 (MAP2) on RT-PCR. Variability was found in the differentiation potential corresponding to the tendency of the original tissue to differentiate. It is suggested that the cell type should be selected depending on the regenerative treatment regimen.

Development and external validation of a nomogram for overall survival after curative resection in serosa-negative, locally advanced gastric cancer.

BACKGROUND: Few nomograms can predict overall survival (OS) after curative resection of advanced gastric cancer (AGC), and these nomograms were developed using data from only a few large centers over a long time period. The aim of this study was to develop and externally validate an elaborative nomogram that predicts 5-year OS after curative resection for serosa-negative, locally AGC using a large amount of data from multiple centers in Japan over a short time period (2001-2003). PATIENTS AND METHODS: Of 39 859 patients who underwent surgery for gastric cancer between 2001 and 2003 at multiple centers in Japan, we retrospectively analyzed 5196 patients with serosa-negative AGC who underwent Resection A according to the 13th Japanese Classification of Gastric Carcinoma. The data of 3085 patients who underwent surgery from 2001 to 2002 were used as a training set for the construction of a nomogram and Web software. The data of 2111 patients who underwent surgery in 2003 were used as an external validation set. RESULTS: Age at operation, gender, tumor size and location, macroscopic type, histological type, depth of invasion, number of positive and examined lymph nodes, and lymphovascular invasion, but not the extent of lymphadenectomy, were associated with OS. Discrimination of the developed nomogram was superior to that of the TNM classification (concordance indices of 0.68 versus 0.61; P < 0.001). Moreover, calibration was accurate. CONCLUSIONS: We have developed and externally validated an elaborative nomogram that predicts the 5-year OS of postoperative serosa-negative AGC. This nomogram would be helpful in the assessment of individual risks and in the consideration of additional therapy in clinical practice, and we have created freely available Web software to more easily and quickly predict OS and to draw a survival curve for these purposes.

The effects of C-type natriuretic peptide on craniofacial skeletogenesis.

C-type natriuretic peptide (CNP) is a potent stimulator of long bone and vertebral development via endochondral ossification. In the present study, we investigated the effects of CNP on craniofacial skeletogenesis, which consists of both endochondral and membranous ossification. Morphometric analyses of crania from CNP knockout and transgenic mice revealed that CNP stimulates longitudinal growth along the cranial length, but does not regulate cranial width. CNP markedly increased the length of spheno-occipital synchondrosis in fetal murine organ cultures, and the thickness of cultured murine chondrocytes from the spheno-occipital synchondrosis or nasal septum, resulting in the stimulation of longitudinal cranial growth. Mandibular growth includes endochondral and membranous ossification; although CNP stimulated endochondral bone growth of condylar cartilage in cultured fetal murine mandibles, differences in the lengths of the lower jaw between CNP knockout or transgenic mice and wild-type mice were smaller than those observed for the lengths of the upper jaw. These results indicate that CNP primarily stimulates endochondral ossification in the craniofacial region and is crucial for midfacial skeletogenesis.

Frequent STAT3 activation is associated with Mcl-1 expression in nasal NK-cell lymphoma.

Nasal natural killer (NK)-cell lymphoma was resistant to various antitumor agents. Although high expression of p-glycoprotein has been reported, other molecular mechanism of the chemo-resistance is largely unknown. Activation of STAT3 and expression of major apoptosis-related proteins Bcl-2, Bcl-x, and Mcl-1 were analyzed by immunohistochemistry. Effects of STAT3 inhibitor AG490 on NK-YS cell line were analyzed by Western blotting and flow cytometric apoptosis assay. STAT3 was activated in six of the nine nasal NK-cell lymphomas (67%). In contrast, STAT3 activation was detected in 35% of diffuse large B-cell lymphoma (DLBCL) and in 10% of follicular lymphoma (FL). Frequent activation of STAT3 was significantly correlated with Mcl-1 expression in nasal NK-cell lymphoma, i.e., Mcl-1 was positive in five of six STAT3-active cases and negative in all three STAT3-inactive ones. In DLBCL, not only six out of seven STAT3-active cases (86%) but also eight out of thirteen STAT3-inactive cases (62%) were positive for Mcl-1 expression. Latent membrane protein-1 was positive in four nasal NK-cell lymphomas, among which three cases showed intermediate STAT3 activation. Inhibition of STAT3 activation by JAK inhibitor AG490 decreased Mcl-1 expression and induced apoptosis in STAT3-active NK-YS cells. Serum starvation rather increased the Mcl-1 level in NK-YS cells, and this effect was also canceled by AG490. These results suggest that activation of STAT3-Mcl-1 axis may play a role in the chemotherapy resistance of nasal NK-cell lymphoma. The pathway may be one of the future therapeutic targets of this intractable disease.

Central nervous system is a sanctuary site for chronic myelogenous leukaemia treated with imatinib mesylate.

Imatinib mesylate (IM) is currently used as the first therapeutic choice against chronic myelogenous leukaemia (CML). Because IM poorly penetrates the blood-brain barrier, IM-treated CML patients may have a potential risk of central nervous system (CNS) involvement. Here we report a case with lymphoid blast crisis isolated only in CNS after bacterial meningitis, although the patient achieved and maintained complete cytogenetic response by IM therapy. It is important to consider isolated CNS blast crisis as a possible event in IM-treated CML patients.

Spontaneous regression of natural killer cell lymphoma.

Spontaneous tumour regression is extremely rare in aggressive lymphoma. A case of natural killer (NK) cell lymphoma with cutaneous manifestation showed an indolent clinical course, and the relapsed nodular lesion disappeared spontaneously without any treatment. Although only small number of T cells were present in the primary skin lesion, there was massive CD8-positive cytotoxic T cell infiltration in the relapsed lesion. This is believed to be the first report of an abscopal effect on NK cell lymphoma. Infiltration of cytotoxic T cells strongly suggests immunological attack against the lymphoma cells.

Epstein-Barr virus renders the infected natural killer cell line, NKL resistant to doxorubicin-induced apoptosis.

We established two Epstein-Barr virus (EBV)-infected NKL sublines, which acquired stress resistant phenotype against DNA damage and starvation compared with EBV-negative NKL. EBV-rendered doxorubicin resistance at least partially through NF-kappaB activation and the resultant sustenance of antiapoptotic proteins including Bcl-X(L) and FLIP(L/S).

Hsp90-inhibitor geldanamycin abrogates G2 arrest in p53-negative leukemia cell lines through the depletion of Chk1.

Checkpoint protein Chk1 has been identified as an Hsp90 client. Treatment with 100 nM geldanamycin (GM) for 24 h markedly reduced the Chk1 amount in Jurkat and ML-1 leukemia cell lines. Because Chk1 plays a central role in G2 checkpoint, we added GM to G2-arrested Jurkat and HL-60 cells pretreated with 50 nM doxorubicin for 24 h. GM slowly released both cell lines from doxorubicin-induced G2 arrest into G1 phase. GM also abrogated ICRF-193-induced decatenation G2 checkpoint in Jurkat and HL-60 cells. Western blot analysis showed that addition of GM attenuates doxorubicin- and ICRF-193-induced Chk1 phosphorylation at Ser345. GM, however, failed to abrogate G2 arrest in p53-positive ML-1 cells maybe due to the p21 induction. GM released HeLa cells from doxorubicin-induced G2 arrest but trapped them at M phase. Flow cytometric analysis showed that addition of GM converted doxorubicin-induced necrosis into apoptosis in Jurkat cells. Colony assay indicated that although GM has a weak cytotoxic effect as a single agent, it dramatically intensifies the cytotoxicity of doxorubicin and ICRF-193 in Jurkat and HL-60 cells. These results suggest that abrogation of G2 checkpoint by GM may play a central role in sensitizing p53-negative tumor cells to DNA-damaging and decatenation-inhibiting agents.

Hepatic hyperplastic nodules showing stains by portal blood flow: hemodynamics revealed by CTAP and CTHA.

The hepatic hyperplastic nodule associated with idiopathic portal hypertension is classified as portal blood flow and hepatic arterial blood flow dominant types. These nodular lesions are considered attributable to abnormal blood flow in the liver. We describe a rare case of hepatic hyperplastic nodules showing stains by portal blood flow.

DNA microarray analysis of natural killer cell-type lymphoproliferative disease of granular lymphocytes with purified CD3-CD56+ fractions.

Natural killer (NK) cell-type lymphoproliferative disease of granular lymphocytes (LDGL) is characterized by the outgrowth of CD3(-)CD16/56(+) NK cells, and can be further subdivided into two distinct categories: aggressive NK cell leukemia (ANKL) and chronic NK lymphocytosis (CNKL). To gain insights into the pathophysiology of NK cell-type LDGL, we here purified CD3(-)CD56(+) fractions from healthy individuals (n=9) and those with CNKL (n=9) or ANKL (n=1), and compared the expression profiles of >12 000 genes. A total of 15 'LDGL-associated genes' were identified, and a correspondence analysis on such genes could clearly indicate that LDGL samples share a 'molecular signature' distinct from that of normal NK cells. With a newly invented class prediction algorithm, 'weighted distance method', all 19 samples received a clinically matched diagnosis, and, furthermore, a detailed cross-validation trial for the prediction of normal or CNKL status could achieve a high accuracy (77.8%). By applying another statistical approach, we could extract other sets of genes, expression of which was specific to either normal or LDGL NK cells. Together with sophisticated statistical methods, gene expression profiling of a background-matched NK cell fraction thus provides us a wealth of information for the LDGL condition.

Ureteral fibroepithelial polyp associated with urolithiasis induced by steroid therapy in a child: a case report.

A 14-year-old boy complained of left flank pain. He had been given high-dose corticosteroid therapy for chronic inflammatory demyelinating polyneuropathy (CIDP). Retrograde pyelography revealed irregular defects at the left ureteropelvic junction (UPJ), and ureteroscopy demonstrated ureteral polyp. The polyp was removed and histologically diagnosed as fibroepithelial polyp. Hypercalciuria due to the corticosteroids and bedridden was assumed to have been a causative factor in the stone formation. To our knowledge, this is the first report of a ureteral fibroepithelial polyp in children associated with urolithiasis, and associated with CIDP.

Circadian rhythm of melatonin release in pineal gland culture: arg-vasopressin inhibits melatonin release.

The mammalian pineal gland is known to receive a noradrenergic sympathetic efferent signal from the suprachiasmatic nucleus (SCN) via the superior cervical ganglion. Arg-vasopressin (AVP) containing neurons in the SCN is one of the output paths of circadian information to the other brain areas. AVP release from the SCN is suppressed by melatonin. In turn, we determined the direct effect of AVP on melatonin release using pineal gland explant culture. AVP (1 microM) suppressed melatonin release. Noradrenaline stimulated melatonin release was attenuated by AVP. In turn, the expression of the melatonin synthesis enzyme arylalkylamine N-acetyltransferase mRNA in the rat SCN was reported. We measured melatonin content in the SCN in rats kept under the light-dark cycle and constant dim light. Melatonin in the SCN was higher during the dark period than that in the light. A similar tendency was also observed in the SCN of animals kept under a constant dim light. It was suggested that the reciprocal regulation of melatonin release and AVP release occurs in the SCN and pineal gland.

Taste-enhancing effects of glycine on the sweetness of glucose: a gustatory aspect of symbiosis between the ant, Camponotus japonicus, and the larvae of the lycaenid butterfly, Niphanda fusca.

The lycaenid butterfly, Niphanda fusca, has a parasitic relationship with its host ant, Camponotus japonicus: the caterpillars may use chemical mimicry to enter the ant nest where they are fed mouth-to-mouth by the adult ants until pupation. Nevertheless, larvae offer their host ants a nutritious secretion that contains 160 mM glucose and 43 mM glycine. Using glucose and glycine mixture as artificial secretions, we investigated the gustatory effect of glucose and/or glycine on the ants. Glycine induced neither feeding behavior nor gustatory response in the ants if its concentration was <500 mM. In the presence of glycine at the concentration in the secretion, however, the ants improved their preference to glucose, and the sugar receptor cell exhibited electrophysiological enhancement of response to glucose in a glycine-concentration-dependent manner. By adding glycine to glucose in their secretions, therefore, the butterfly larvae can manipulate the gustatory sense of the ants. The alluring taste of 'glycine-flavored glucose' could motivate the host ants to feed the larvae and thereby receive the secretions as a reward. The taste enhancement created by the combination of sugar and amino acid may play a role in the evolution of the parasitic relationships of these insects. The taste-enhancing effect appears to be analogous to taste enhancement by 'umami' substances in humans.

Properties of an extracellular polysaccharide produced by a strain of enterobacter isolated from pond water.

A bacterium which was isolated from pond water and identified as Enterobacter cloacae produced a viscous extracellular polysaccharide when it was grown aerobically in a medium containing sucrose as a sole source of carbon. The maximum molecular weight of the polysaccharide was about 9.0 x 10(5). The polysaccharide was composed of fucose, galactose, glucose, and glucuronic acid in a molar ratio of 2:3:2:1, but the molecular weight and the molar ratio of the sugar component were different from those of the polysaccharide produced by the same species reported elsewhere.

Pharmacological characterization of a novel 5-HT4 receptor agonist, TS-951, in vitro.

The pharmacological effect of a novel selective 5-HT4 receptor agonist, TS-951 (N-[endo-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]oct-3-yl]-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide) was investigated in vitro. TS-951 potently inhibited specific [3H]GR113808 binding both in guinea-pig striatum and in mouse brain. The affinity of TS-951 for the 5-HT4 receptor was higher than those of other agonists, 5-HT, cisapride, mosapride and renzapride. On the longitudinal muscle of the guinea-pig ileum, TS-951 caused a concentration-dependent increase in the amplitude of electrically induced submaximal twitch contractions. On the longitudinal muscle of the guinea-pig distal colon, TS-951 also caused concentration-dependent contractions. TS-951 is a high-affinity, selective and potent 5-HT4 receptor agonist. This compound therefore can be considered as a useful pharmacological tool for investigating 5-HT4 receptor-mediated events.